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REVIEW
Cigarette smoke and adverse health effects:
An overview of research trends and future needs
Sibu P Saha MD MBA FICA1, Deepak K Bhalla PhD2, Thomas F Whayne Jr MD PhD FICA1, CG Gairola PhD3
SP Saha, DK Bhalla, TF Whayne Jr, CG Gairola. Cigarette
smoke and adverse health effects: An overview of research
trends and future needs. Int J Angiol 2007;16(3):77-83.
A large volume of data has accumulated on the issues of tobacco and
health worldwide. The relationship between tobacco use and health
stems initially from clinical observations about lung cancer, the first
disease definitively linked to tobacco use. Almost 35 years ago, the
Office of the Surgeon General of the United States Health Service
reviewed over 7000 research papers on the topic of smoking and
health, and publicly recognized the role of smoking in various dis-
eases, including lung cancer. Since then, numerous studies have been
published that substantiate the strong association of tobacco use with a
repository for the collection, analysis, validation and dis-
A semination of all smoking and health-related data was
established by the World Health Organization. The data
received from various member countries were compiled into a
book entitled Tobacco or Health: A Global Status Report, 1997
(1). This report showed smoking prevalence and other tobacco
use-related data from various countries and presented an analy-
sis. It is estimated that there are approximately 1.1 billion
smokers worldwide, of which 900 million are men and 200 mil-
lion are women. The sex ratio of men to women is 2:1 for
developed nations and 7:1 for developing nations. Smoking
prevalence in men and women averages 42% and 24%, respec-
tively, for developed countries, and 48% and 7%, respectively,
for less developed countries. In comparison, approximately
47 million people smoke cigarettes in the United States (2),
and smoking prevalence in the United States is estimated at
28% and 23% for men and women, respectively. The Surgeon
General’s report in 2004 concluded that in the United States,
cigarette smoking has caused 12 million deaths since 1964, at
a cost to the nation of approximately US$157.7 billion each
year (3). There has been a significant decline in the consump-
tion of cigarettes in the United States since 1964. The produc-
tion of cigarettes continues at a steady pace mainly to meet
export demands, which continue to rise due to increasing
tobacco use in the rest of the world, especially in far eastern
and southeastern Asia. On the basis of consumption and dis-
ease incidence trends, it is predicted that there will be an epi-
demic of tobacco-related diseases in various countries of the
world in the next 20 to 30 years.
1GillHeart Institute, University of Kentucky, Lexington, Kentucky; 2Department of Pharmaceutical Sciences, Wayne State University, Detroit,
Michigan; 3Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, USA
Correspondence: Dr Sibu P Saha, Gill Heart Institute, University of Kentucky, 900 Limestone Street, Suite 407, Lexington, Kentucky
40536-0200. Telephone 859-278-1227, fax 859-278-4836, e-mail ssaha2@uky.edu
Int J Angiol Vol 16 No 3 Autumn 2007 ©2008 Pulsus Group Inc. All rights reserved
variety of adverse human health effects, most prominently with can-
cer and cardiovascular diseases. Cigarette smoking is regarded as a
major risk factor in the development of lung cancer, which is the
main cause of cancer deaths in men and women in the United States
and the world. Major advances have been made by applying modern
genetic technologies to examine the relationship between exposure
to tobacco smoke and the development of diseases in human popula-
tions. The present review summarizes the major research areas of the
past decade, important advances, future research needs and federal
funding trends.
Key Words: Atherosclerosis; Cancer; Smoking; Tobacco
EPIDEMIOLOGY OF
TOBACCO-RELATED DISEASE
As part of the Global Burden of Disease Study carried out by
the Harvard University School of Public Health in 1997 (4), it
was projected that mortality and morbidity from tobacco use
will increase by almost threefold worldwide in 20 to 25 years.
Similar predictions have been made by the Oxford University
Center headed by Sir Richard Doll, who was one of the first
researchers to link cigarette smoking with lung cancer in the
1950s (5,6). Cancer, cardiovascular diseases and chronic
obstructive pulmonary disease continue to be the main health
problems associated with cigarette smoking. An extensive
database has accumulated, which has consistently documented
a relationship between smoking and these specific diseases.
The strength of the association is further demonstrated by
measuring the RR and the presence of a dose-response rela-
tionship (ie, direct relationship between the intensity of expo-
sure to cigarette smoke and the risk of disease). According to a
2004 Centers for Disease Control and Prevention report (3),
approximately 2600 people die of cardiovascular disease in the
United States every day, which translates into one death every
33 s. Furthermore, the likelihood of dying from heart disease
increases fourfold as a result of smoking. The cost of heart dis-
ease and stroke in terms of health care expenses and lost pro-
ductivity was estimated at US$351 billion in the United States
alone in 2003.
An analysis by European health experts (7) determined
that in developed countries as a whole, tobacco is responsible
for 24% of all male deaths and 7% of all female deaths; these
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Saha et al
figures rise to over 40% in men in some countries of central
and eastern Europe and to 17% in women in the United
States. The average decreased life span of smokers is approxi-
mately eight years. Among United Kingdom doctors followed
for 40 years, overall death rates in middle age were approxi-
mately three times higher among physicians who smoked ciga-
rettes than in nonsmokers. In those United Kingdom
physicians who stopped smoking, even in middle age, a sub-
stantial improvement in life expectancy was noticed. These
same experts found that worldwide, smoking kills three million
people each year and this figure is increasing. They predict that
in most countries, the worst is yet to come, because by the time
the young smokers of today reach middle or old age, there will
be approximately 10 million deaths per year from tobacco use.
Approximately 500 million individuals alive today can expect
to be killed by tobacco and 250 million of these deaths will
occur in the middle age group. Tobacco is already the biggest
cause of adult death in developed countries. Over the next few
decades tobacco is expected to become the biggest cause of
adult death in the world. For men in developed countries, the
full effects of smoking can already be seen. Tobacco causes one-
third of all male deaths in the middle age group (plus one-fifth
in the old age group) and is the cause of approximately one-
half of all male cancer deaths in the middle age group (plus
one-third in the old age group). Of those who start smoking in
their teenage years and continue smoking, approximately one-
half will be killed by tobacco. One-half of these deaths will be
in middle-aged individuals (35 to 69 years of age) and each will
lose an average of 20 to 25 years of nonsmoker life expectancy.
In contrast, the total mortality is decreasing rapidly and cancer
mortality is decreasing slowly in nonsmokers in many coun-
tries. Throughout Europe in the 1990s, tobacco smoking
caused three-quarters of a million deaths in the middle age
group. In the Member States of the European Union in the
1990s, there were over one-quarter of a million deaths in the
middle age group directly caused by tobacco smoking, which
included 219,700 deaths in men and 31,900 in women. There
were many more deaths caused by tobacco at older ages. In
countries of central and eastern Europe, including the former
Union of Soviet Socialist Republics, there were 441,200
deaths in middle-aged men and 42,100 deaths in women.
Several epidemiological studies examining the factors respon-
sible for the interindividual differences in the susceptibility to
tobacco-related cancers and cardiovascular diseases are being
performed in the United States, Europe and Japan. Although
still not common practice, many of the newer studies are
employing molecular genetic assays in conjunction with epi-
demiology to identify genotypes susceptible to disease develop-
ment and select suitable biomarkers of tobacco smoke
exposure.
The frequency of investigations in the area of cigarette
smoke composition and chemistry decreased during the last
decade. Nonetheless, there are ample data to suggest that ciga-
rette smoke is a highly complex mixture that contains approx-
imately 4800 different compounds (8). Approximately 100 of
these compounds are known carcinogens, cocarcinogens
and/or mutagens. The complex mixture also contains gases
such as ozone, formaldehyde, ammonia, carbon monoxide,
toluene and benzene, and about 1010 particles of different sizes
in each mL of mainstream smoke. In addition, a number of
other toxic, mutagenic, tumour promoter and/or cocarcino-
genic substances have been identified in both mainstream and
sidestream cigarette smoke over the years. Many chemical and
biological assays of smoke condensates have also documented
78
the presence of potent inhibitors of carcinogenesis in smoke.
Such a complex chemical composition of smoke has made it
difficult to determine the active constituent(s) responsible for
the tobacco-related health risks of smoking and has led to stud-
ies of individual constituents of smoke such as polycyclic aro-
matic hydrocarbons (PAH), nitrosamines and nicotine. Thus,
over the years, various individual groups of smoke constituents
have been the focus of research at different times. For example,
studies of PAH were in vogue during the 1970s and 1980s, fol-
lowed by nitrosamines in the 1990s. Tobacco alkaloids have
long been studied because of their pharmacological activity
and have attracted increased attention because of their sus-
pected role in addiction, smoking behaviour and cessation.
However, it is also being realized now that the health effects of
this complex mixture are likely to result from a combined
effect of these chemicals through multiple mechanisms rather
than as result of the effects of a single smoke constituent. The
mixture contains compounds belonging to almost every class of
chemicals that are toxic and protective, agonist and antago-
nist, carcinogenic and anticarcinogenic, and exists in the
gaseous as well as the particulate phase. Extensive studies on
the chemical constituents of tobacco smoke and their relation-
ship to disease were published by Hoffmann and Hoffmann of
the American Health Foundation (8). Newer studies have
largely focused on the comparative chemistry of mainstream
and sidestream smoke. Interest in the free radical chemistry of
smoke has resurfaced due to the realization that smoke-
induced oxidative injury may play an important role in the eti-
ology of a variety of tobacco-related diseases. Pioneering
studies on the free radical chemistry of tobacco smoke, per-
formed in the laboratory of William Pryor at the Louisiana
State University (9), identified short- and long-lived radicals
in mainstream and sidestream cigarette smoke, and implicated
them in various smoking-associated disease etiologies.
TOBACCO-RELATED
CARDIOVASCULAR DISEASE
Cardiovascular diseases, and atherosclerosis in particular, are
the leading causes of death in industrial societies. The pre-
dominant underlying cause of coronary artery disease (CAD) is
atherogenesis, which also causes atherosclerotic aortic and
peripheral vascular diseases. Cigarette smoking, independently
and synergistically with other risk factors such as hypertension
and hypercholesterolemia, contributes to the development and
promotion of the atherosclerotic process. Various studies have
shown that the risk of developing CAD increases with the
number of cigarettes smoked per day, total number of smoking
years and the age of initiation, thus indicating a dose-related
response. In contrast, cessation of smoking is reported to
reduce mortality and morbidity from atherosclerotic vascular
disease.
The mechanisms through which smoking influences the
development and progression of atherosclerosis are poorly
understood at present, but recent studies point to an adverse
effect of smoking on endothelial and smooth muscle cell
functions as well as thrombotic disturbances produced by
tobacco smoke (10,11). With the use of modern ultrasono-
graphic techniques, three independent studies performed in
the United States, Europe and Australia have demonstrated
that both active and passive smokers exhibit impaired
endothelium-dependent vasoregulation (12-14). Some
degree of recovery of endothelial function in ex-passive
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smokers who have stayed away from smoke-contaminated
environments further supported a secondary role of smoke in
endothelial dysfunction (15).
Evidence has been presented that tobacco-related impair-
ment of endothelial function may be related to its adverse
effects on endothelial nitric oxide (NO) synthase (16,17). An
association between a genetic polymorphism of the endothelial
NO synthase gene and the predisposition of smokers to CAD
was reported (18,19). Additionally, studies report that smoke
interferes with L-arginine and NO metabolism, resulting in
reduced NO formation (20). Upregulation of the expression of
endothelial cell adhesion molecules (CAMs) such as vascular
CAM-1 and intercellular CAM-1 by smoke condensates, and
stimulation of leukocyte and endothelium attachment by
exposure to cigarette smoke was demonstrated (21). Cigarette
smoke extract has been shown to induce expression of CAMs
(22). However, the expression of a specific adhesion molecule
is determined in vivo and the relationship between various
events is poorly understood.
Exposure to tobacco smoke is known to increase oxidative
stress in the body by various mechanisms, including deple-
tion of plasma antioxidants such as vitamin C. At least two
studies have been performed to determine the role of oxida-
tive stress in increasing leukocyte-endothelial interactions
that precede the development of atherosclerosis in smokers.
One study showed that a high intake of vitamin C by smok-
ers significantly reduced the adhesiveness of their monocytes
to endothelial cells (23). However, in a second study, sera
from young smokers was collected before and after a single
oral supplementation with vitamin C and L-arginine (a sub-
strate for NO production). The sera were tested for promo-
tion of the adherence of human monocytes to human
umbilical vein endothelial cell monolayers. It was shown that
while oral L-arginine caused reduction in such leukocyte
adherence, no reduction was seen with vitamin C supplemen-
tation (24). This suggested that the NO levels may be impor-
tant in smoking-induced leukocyte-endothelial interactions, at
least during the early stages. Neither NO nor any other mark-
ers of oxidative stress were measured in either of these studies.
The levels of 8-hydroxydeoxyguanosine, an oxidized DNA
product, and F2-isoprostane, an oxidative arachidonic acid
product, were found to be elevated in passive smokers (25,26).
Oxidation of low-density lipoprotein (LDL), which is a gold
standard risk factor of the atherosclerotic process, was also
found to be elevated in smokers, as determined by the presence
of increased levels of autoantibodies against oxidized LDL. It
was further demonstrated that dietary supplementation with a
lipid-soluble antioxidant, α-tocopherol, significantly reduced
plasma levels of oxidized LDL autoantibodies (27). Similarly,
intake of a mixture of antioxidants was found to increase the
resistance of smoker LDL to oxidative modification (28) and
reduce the plasma levels of 8-hydroxydeoxyguanosine in pas-
sive smokers (25). These studies have thus identified newer,
more specific markers of oxidative stress that can be used as
biomarkers of oxidant injury and used for the development of
dietary and/or pharmacological interventions against disease
development.
Relatively few studies related to cardiovascular effects of
cigarette smoke have been performed in rodent models. Such
animal studies are, however, needed to delineate the role of
different mechanisms in promoting atherosclerotic disease and
for developing appropriate interventions.
Int J Angiol Vol 16 No 3 Autumn 2007
Cigarette smoke and adverse health effects
TOBACCO-RELATED CANCERS
Tobacco carcinogenesis has remained a focus of research dur-
ing the past 10 years, and various epidemiological and experi-
mental studies have not only confirmed the major role of
tobacco smoke exposure in lung and bladder cancers, but have
also reported on its association with cancers of various other
sites, such as the oral cavity, esophagus, colon, pancreas,
breast, larynx and kidney. It is also associated with leukemia,
especially acute myeloid leukemia.
In addition to the highly recognized role of cigarette smok-
ing in lung cancer, it has been implicated in many other
chronic diseases, including chronic bronchitis and pulmonary
emphysema. In the United States, the reduction in smoking
has resulted in a decline in death due to lung cancer in men
since the mid 1980s. However, the incidence of lung cancer in
women has surpassed that of breast cancer and continues to
rise; it will likely be the focus of future studies (29,30). Both
active and passive smoking are implicated in this increase, and
several studies of smoking behaviour and disease incidence in
women suggest greater susceptibility of women to tobacco car-
cinogens (31). It is believed that 80% to 90% of all respiratory
cancers are related to active smoking.
Because of the antiestrogenic protective effects of smoking,
the role of smoking in breast cancer is controversial. However,
recent studies suggest that both active and passive smoking
may have a role in the occurrence of breast cancer. One exam-
ple is a study that found an OR of 4.5 for breast cancer among
women who were exposed to passive smoke before 12 years of
age and an OR of 7.5 for active smokers. Women who were
first exposed to passive smoke after 12 years of age had a lower,
although still elevated, OR (32).
In both men and women, cancers of the head and neck are
also on the rise, and this has been attributed to increased use of
smokeless tobacco products. Also, a synergistic interaction
between cigarette smoking and radon exposure was confirmed
in a large study that showed that lung cancer incidence due to
an interaction between smoking and radon exposure exceeded
incidence accounted for by additive effects and, therefore,
indicated multiplicative effects (33).
Comparative toxicity studies have shown that in compari-
son with standard cigarettes, the new experimental cigarettes
that heat tobacco have a relatively low toxicity (34). In com-
paring lung cancer risk in smokers of different types of ciga-
rettes, Lee (35) determined in 2001 that the risk was 36%
lower in individuals smoking filtered cigarettes than in those
smoking unfiltered cigarettes, and the risk was 23% lower for
smokers of low-tar cigarettes than smokers of high-tar ciga-
rettes. The risk increased by 42% in hand-rolled cigarette
smokers and by 75% in smokers using black tobacco.
One interesting observation relates to the nature of lung
cancer, which has changed over the years with respect to the
location and the types of lung tumours observed in smokers. In
the past, the primary tumours observed among smokers were
the centrally located squamous cell carcinomas of the airways.
Now, the predominant lung tumours in smokers are peripheral
adenocarcinomas and other non-small-cell lung cancers. This
shift in tumour types has been attributed to changes in the
composition of cigarettes and its effect on the smoking pat-
terns of tobacco users over the past 30 years (8,36).
Significant reductions in cigarette tar and nicotine and
increased levels of nitrates in cigarettes have markedly altered
the manner in which cigarettes are smoked. The number and
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Saha et al
volume of puffs taken by smokers have increased from a single
35 mL puff/min with 1950s cigarettes to two to four 50 mL
puffs/min of low-tar or low-nicotine cigarettes; the depth of
inhalation has also increased. These changes in smoking pat-
terns have promoted greater deposition of smoke constituents
into the peripheral lungs, where adenocarcinomas develop.
Major advances are being made in the area of molecular epi-
demiology of tobacco-related cancers in human populations.
Many recent epidemiological studies have focused on the differ-
ential susceptibility to tobacco-related cancers; they have
employed polymerase chain reaction-based molecular assays that
permit genotypic analysis of small human samples and supple-
ment the information generated by enzymatic and immunologi-
cal assays. These assays are increasingly being used in human
and experimental studies to examine various gene-gene and
gene-environment interactions. One area that has received con-
siderable attention in recent years is the role of polymorphic
enzymes in the development of diseases. It is now well recog-
nized that genetic polymorphism strongly influences cancer sus-
ceptibility and incidence. The frequencies of mutated alleles of
proto-oncogenes, tumour suppressor genes and xenobiotic bio-
transformation genes vary significantly among different popula-
tions and impact substantially on their susceptibility to cancer.
Nearly every enzyme in the carcinogen metabolism pathways
has been found to exist in multiple forms, many of which vary in
binding affinity and/or turnover efficiency. Some are even
entirely absent in individuals, thereby influencing their suscep-
tibility to disease development.
The chemical complexity of tobacco smoke and the meta-
bolic activation requirements for many of its carcinogenic
constituents have drawn particular attention to genetic poly-
morphisms of biotransformation enzymes that metabolize
tobacco smoke carcinogens. Thus, genes for various activat-
ing enzymes such as cytochrome P450 (CYP) proteins, and
deactivating enzymes such as glutathione S-transferase
(GST), N-acetyl transferase (NAT) and uridine diphosphate-
glucose transferase have been the main target of many recent
studies in the context of tobacco carcinogenesis. Also, pre-
existing inherited mutations and/or mutation susceptibility of
tumour suppressor genes such as p53, which are known to play
a major role in determining cancer susceptibility, have been a
subject of investigations in tobacco-related carcinogenesis
(37,38).
Several human studies have suggested a strong interplay of
various polymorphic CYP1A1, CYP1A2, CYP2E1, NAT1,
NAT2, GSTM1 and GSTT1 enzymes in modulating the for-
mation of DNA adducts, induction of mutations and chromo-
somal damage, and/or the incidence of cancers of various sites
in different populations (39-47).
The CYP1A1 gene has been extensively studied in Japanese
populations. Two polymorphic variants that interact with
smoking to modify lung cancer risk have been identified
(47,48). Thus, a homozygous minor allele combined with
smoking was found to increase lung cancer risk. Studies of the
same gene in Western populations have, however, yielded neg-
ative or conflicting results (49), although an interaction of
CYP1A1 variants with the GST null genotype has been
reported to significantly increase lung cancer risks in non-
Japanese populations (50,51).
NATs are polymorphic conjugation enzymes (produced by
the NAT1 and NAT2 genes) involved in the detoxification of
aromatic amines by N-acetylation. Depending on the presence
80
or absence of a particular variant, individuals can be catego-
rized as slow or fast acetylators, which in turn can influence the
incidence of bladder cancer. It was shown that slow acetylator
NAT2 is an important modifier of the amount of aromatic
amine-DNA adduct formation even at a low dose of tobacco
smoke exposure (52). Slow acetylator NAT2 genotype was also
a significant risk factor for bladder cancer in moderate and
heavy smokers, but had no effect in nonsmokers (53).
GSTs are another group of metabolic detoxification
enzymes that have attracted a great deal of interest in recent
years because of their association with risks for different types
of cancers. Based on their sequences, these enzymes are divided
into five classes. Three of these classes – GSTM1, GSTT1 and
GSTPi – are important in the context of tobacco-related can-
cers. Extensive studies on the relationship of these genes to
cancer risks have shown that most populations studied have
very high frequencies (20% to 50%) of homozygous GSTM1
and GSTT1 deletion carriers. GSTM1 and GSTT1 may be
involved in the etiology of cancer at more than one site.
Furthermore, the risk to individuals who carry homozygous
deletions is generally small but increases significantly on inter-
action with cigarette smoking (54). Among all metabolic can-
cer susceptibility genes, the association of GSTM1 deficiency
with cancer risk is the most consistent and unidirectional.
Various experimental and epidemiological observations sup-
port the role of this gene in tobacco-related cancers. For exam-
ple, it has been observed that the excretion of urinary
mutagens and the number of lung tissue DNA adducts in
GSTM1-deficient smokers is significantly greater than those
carrying the wild-type allele (55-57). Various epidemiological
studies also support the premise that deficiency of this enzyme
predisposes for lung and bladder cancers (58). Furthermore,
low activity alleles of GSTPi have been often found in associ-
ation with different types of human cancers (59,60).
In addition to anomalies of biotransformation enzyme
genes, inactivation of tumour suppressor genes such as p53, and
activation of the proto-oncogene K-ras are also involved in
tobacco-related cancers. Various mutated forms of tumour sup-
pressor gene p53 have been commonly detected in lung
tumours and it has been found that these mutations are pre-
dominantly located in exons 5 to 8. The nature of point muta-
tions in this gene has been extensively investigated and studies
show that the most common mutant allele of the p53 gene pos-
sesses a G:C to A:C transversion (61), which is associated with
tobacco use (62,63).
The above studies show that several genetically controlled
polymorphic enzymes and enzyme systems are linked to tobacco
carcinogen activation and deactivation. Some of these genes
have been identified and characterized, but others remain undis-
covered. Not only the independent effects of single gene poly-
morphisms, but an interplay of multiple gene interactions appear
to be involved. The complexity of epidemiological studies,
which have many uncontrollable variables, makes it difficult to
study such interactions and their control in human studies.
Additionally, many of the enzymes involved in tobacco carcino-
gen metabolism are also induced by other environmental factors
such as alcohol use, dietary constituents, pesticide and xenobi-
otic exposure, hormonal status, etc, further complicating the
interpretation of data. The interaction of many of these genes
with each other and the effect of environmental factors are just
beginning to be examined. Experimental studies in specifically
constructed transgenic and knock-out animals will be important
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for a systematic evaluation of the contribution of specific can-
cer genes and/or cancer susceptibility genes to the tobacco car-
cinogenic process, and to help identify the mechanisms
through which environmental agents, such as cigarette smoke,
influence these processes.
SECONDHAND SMOKE
The adverse effects of cigarette smoke on human health are
widely recognized. It is the main etiological agent in chronic
obstructive pulmonary disease and lung cancer, and is a known
human carcinogen. While the risks to human health from active
smoking are accepted, evidence supporting the risk of involun-
tary exposure to environmental tobacco smoke (ETS) has accu-
mulated in recent years. It is the main source of toxicant
exposure by inhalation in nonsmokers. Despite recent regula-
tions, smoking in public enterprises is not uncommon. However,
despite an occasional report on the effect of secondhand smoke
in nonsmokers, little attention was given to this aspect of smok-
ing until about 1970. ETS is now regarded as a risk factor for
development of lung cancer, cardiovascular disease and altered
lung functions in passive smokers (64). In general, children
exposed to ETS show deterioration of lung function, more days
of restricted activity, more pulmonary infections, more days in
bed, more absences from school and more hospitalization than
children living in nonsmoking homes (65).
Passive smoking is also implicated in increasing atherosclero-
sis in individuals 15 to 65 years of age. Children exposed to ETS
are at higher risk of developing cardiovascular disorders.
Quantitative risk estimates were obtained by measuring the
intimal-medial thickness of the carotid artery in a large longitu-
dinal atherosclerosis risk study of 10,914 individuals. Increases
of 50%, 25% and 20% were shown over nonsmokers in cur-
rent, ex- and passive smokers, respectively, thus suggesting a role
of all types of tobacco smoke exposure in the progression of ath-
erosclerosis (66). A recent meta-analysis (67) of 18 epidemio-
logical studies (10 cohort and eight case-control) further showed
an increased RR of CAD in ETS-exposed individuals. These
investigators also identified a significant dose-response relation-
ship between the intensity of smoke exposure and risk of CAD
in passive smokers. Cardiovascular health risks of smoke-
exposed women are of particular concern. Although the expo-
sure to ETS is a current topic of debate in tobacco-related
cancers and other lung diseases, the limited research at the basic
experimental level provides a strong argument for launching
experimental studies to support human data and explore disease
mechanisms.
Follow-up of news stories, and local and state ordinances,
leads to the conclusion that more communities and states are
restricting exposure to secondhand smoke.
NATIONAL INSTITUTES OF HEALTH
RESEARCH FUNDING FOR STUDIES OF
HEALTH EFFECTS OF CIGARETTE SMOKE
To determine the extent of federal support for experimental
studies in the area of health effects of cigarette smoke, the
National Institutes of Health (NIH) database of all R01
research grant awards was searched for titles and abstracts con-
taining the words ‘cigarette smoke’ from 1985 to 1998. The
results are summarized below. A total of 127 hits were obtained
and a careful review of the abstracts provided the following dis-
tribution:
Int J Angiol Vol 16 No 3 Autumn 2007
Cigarette smoke and adverse health effects
• Grants involving experimental animal studies = 12
(9.4%)
• Grants involving experimental animal studies in which
whole tobacco smoke was used = 3 (2.3%)
• Grants involving experimental animal studies using
smoke components (nicotine, PAH, cadmium and
quinones) = 8 (6.2%)
• One grant involved aging
A similar search of the NIH database from 1999 to 2006
revealed 907 grants in all award categories. The grant distribu-
tion by category was as follows:
• Total number of R01s = 383
• Grants involving experimental animal studies = 77
(20.1%)
• Grants involving experimental animal studies in which
whole tobacco smoke was used = 29 (7.6%)
• Grants involving experimental animal studies using
smoke components (nicotine, PAH, cadmium and
quinones) = 29 (7.6%)
All the remaining grants generally supported behavioural
and epidemiological studies in humans or other systems.
Although the number of grants supporting animal studies
increased between 1999 and 2006 compared with 1985 to
1998, a significant portion of NIH funding still went to
research projects in the area of tobacco use and smoking
behaviour, tobacco use among youth and interventions, nico-
tine addiction and neurobiology of nicotine (areas not covered
in this review), presumably in agreement with the NIH’s
recent goal of finding effective smoking cessation programs to
reduce tobacco usage in the general population. Thus, it is
clear that the need for basic experimental research in the field
of smoking-associated diseases and the mechanisms through
which tobacco smoke causes various diseases remain as impor-
tant as they ever were. The escalation of health care costs
makes it even more necessary to find ways to protect the
health of smokers and smoke-exposed individuals with any
dietary or therapeutic interventions that hold promise.
DIRECTIONS FOR FUTURE RESEARCH
The most benefit is likely to result from detailed epidemio-
logical studies complemented by specific molecular genotyp-
ing of various populations. Ideally, studies of this type will
re-evaluate the prevalence of smoking and tobacco use and
determine the exact nature of tobacco-related disease inci-
dence, the role of contributory factors such as dietary habits,
exposure to other substances and the genetic composition of
subpopulations most at risk. Various biochemical and molec-
ular assays will need to be applied to screen nonsmoker and
smoker populations for a variety of health risks. Analysis of
the results from such studies will help identify the main
interacting factors for various health risks and define rela-
tionships among various epidemiological parameters. It
would appear necessary to assemble teams of multidiscipli-
nary investigators to perform these coordinated human stud-
ies in the field and in the laboratory. By nature, such studies
are expensive and will involve commitment of resources,
time and substantial amounts of funds to obtain meaningful
results. Given the limited resources and competing priorities
81
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Saha et al
for research funding, it is not easy to undertake such human
studies. Hence, the experimental studies in animal models
using inhalation exposure to whole smoke, and not individ-
ual constituents of smoke, is probably the next best approach
for smoking and health programs.
The human epidemiological studies described in the pres-
ent review have identified a number of genes that appear to
have a distinct role in various tobacco-related diseases, and
cancers in particular. Inability to control all the different vari-
ables in human studies has made it difficult to clearly define
the contribution of various suspect genes in tobacco carcino-
genesis. With the recent commercial availability of a variety of
transgenic and knock-out animals for research, it would be
most desirable, as a first step, to use these animals to establish
experimental models of various tobacco-related diseases which
can then be used for determining the contribution of different
genes to disease processes and for elucidation of the mecha-
nism(s) of disease development. Furthermore, these animal
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